1. Field Of The Invention
The invention relates to a process for the production of 2,4-diamino-6-piperidinylpyrimidine-3-N-oxide (Minoxidil).
2. Background Art
Minoxidil is characterized by an excellent antihypertensive effect [Drugs, 22 (1981), 257]and is known in many countries as an antihypertensive agent. Recently, the use of the compound for therapeutic cosmetic increasingly comes to the fore, since applied externally in dilute solution it effectively stimulates hair growth [Pharm. Ind., 46, (1984), 937, and Pharm. Ind., 47, (1985), 506]. In the technical literature the designation Minoxidil has two meanings since it can be in two tautomeric forms. In Chemical Abstracts the compound was mentioned before 1972 under the name 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine, while after that date it was referred to under the designation 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide. Several processes are known for the production of Minoxidil. One process starts from 2,6-diamino-4-chloropyridimine. By oxidation with, e.g., chloroperbenzoic acid or hydrogen peroxide, the corresponding N-oxides are produced, which are then further reacted (European Published Patent Application No. 0254158). Another known process starts from 2-iminopyrimidine derivatives containing acyl and/or acyloxy groups, e.g., from 6-amino-1,2-dihydro-1-acetoxy-2-imino-4-chloropyrimidine. By reaction with piperidine, the corresponding piperidino compound is produced which is then hydrolyzed (European Published Patent Application No. 0252515). These known processes are either technically very expensive or the yields leave a great deal to be desired.
Another known process is described in J. Org Chem., 40, (1975), 3304. The key product used there is cyanoacetylpiperidinic acid amide, whose carboxyl group must first be made reactive. The materials necessary for this process are not easily available and ar linked to high expense.